Pneumocystis (PC) is an opportunistic fungal pathogen that causes pneumonia (PCP) in immunocompromised individuals and is one of the original AIDS-defining pathogens. Even though the incidence of PCP has dropped with the advent of highly active anti-retroviral therapy, mortality rates due to PCP has not changed and HIV-infected individuals are still susceptible to PCP when they are not compliant with their HIV therapy or when the virus becomes resistant to therapy. Though much is known about Pneumocystis and the immune response to it, there are still large gaps in our understanding of how the organism is recognized and cleared by the immune system. PC has two identifiable life forms, the cyst or ascus that is surrounded by a fungal cell wall composed of ?-glucans and chitin and the trophozoite or spore form that is devoid of a cell wall but unlike most medically relevant fungi has a cell membrane that contains cholesterol rather than the ergosterol. It is well established that both macrophages and dendritic cells recognize the cyst form of PC through the ?-glucan receptor dectin-1. However, the cyst form of the organism represents a small proportion of the total lung burden, particularly late in infection when the trophic forms are as much as 90% of the organisms in the lungs. It is not known how dendritic cells and macrophages recognize the trophic forms of PC. The goal of this project is to identify the receptors that dendritic cells and macrophages use to recognize the trophic forms of PC, particularly early during infection before specific antibody is formed, and whether the trophic forms stimulate the cells to produce immune mediators. Our hypothesis is that the trophic forms of PC bind to one or more c-type lectin receptors (CLRs) via mannosylated proteins resulting in a dampened inflammatory response by suppressing signaling through dectin-1. Two specific aims are proposed to address the hypothesis. Aim 1 will determine whether the trophic forms of PC bind CLR and transmit a signal. Aim 2 will determine the mechanism of suppression of inflammation induced by the trophic forms of PC. Together these aims will provide important new information about whether dendritic cells and macrophages are stimulated by PC or, alternatively, whether the trophic forms dampen immunity and escape innate immune surveillance.